ABSTRACT Epilepsy is a family of chronic neurologic disorders characterized by periodic, unpredictable seizures. Current pharmacotherapy for epilepsy relies on ion channel inhibitors, GABAergics, and compounds of unknown mechanism. Following first-line or dual treatment with these drugs, more than 30% of patients continue to experience seizures. A critical barrier in the epilepsy field is the poor brain penetrance of many promising therapeutics. Indeed, there are a number of large or lipophobic compounds that do not readily enter the brain when given systemically, but which are well known in animal studies to show great promise for controlling seizures when they are administered through direct cannulation of the brain. In the proposed studies, we intend to focus on the development of a new technology that will use endogenous biological mechanisms to actively transport these compounds into the brain. We will focus our efforts on neuropeptide Y (NPY) and oxytocin (OT) because 1) these compounds do not readily enter the brain through passive diffusion, 2) there is evidence that these compounds control seizure activity, 3) we have generated exciting preliminary data supporting the use of our technology to transport these compounds into the brain, and 4) these compounds are excellent prototypes with which to conduct proof-of-concept feasibility studies. The long-term goal of this research program is to develop a safe and effective approach to the delivery of neuropeptide treatments for epilepsy and other neurological disorders to the central nervous system. The completion of these studies will provide a solid foundation for further studies to develop even more advanced formulations. These formulations would further refine our approach to increase the brain penetrance, sustain the release, or compartmentalize to the brain novel neuropeptide therapeutics. As such, this proposal will form the foundation of a new research program which we hope will support a new wave of therapeutics for epilepsy.